Method of drying bioabsorbable coating over stents

ABSTRACT

Various embodiments of methods for coating stents are described herein. Applying a composition including polymer component and solvent to a stent substrate followed by exposing the polymer component to a temperature equal to or greater than a Tg of the polymer component is disclosed. Repeating the applying and exposing one or more times to form a coating with the result that the solvent content of the coating after the final exposing step is at a level suitable for a finished stent is further disclosed.

CROSS REFERENCE

This application is a continuation of U.S. patent application Ser. No.14/659,276 filed Mar. 16, 2015 which is a continuation of U.S.application Ser. No. 14/155,217, now U.S. Pat. No. 8,980,364, filed Jan.14, 2014 which is a continuation of U.S. application Ser. No.12/766,758, now U.S. Pat. No. 8,632,845, which was filed on Apr. 23,2010, which is a continuation-in-part of U.S. application Ser. No.10/856,984, now U.S. Pat. No. 7,807,211, which was filed on May 27,2004, which is a continuation-in-part of U.S. application Ser. No.10/603,794, now U.S. Pat. No. 7,682,647, which was filed on Jun. 25,2003.

U.S. application Ser. No. 12/766,758 is also a continuation-in-part ofU.S. application Ser. No. 10/108,004, which was filed on Mar. 27, 2002.

Furthermore, U.S. application Ser. No. 10/856,984 is also acontinuation-in-part of U.S. application Ser. No. 10/304,360, nowabandoned, which was filed on Nov. 25, 2002, which is a divisional ofU.S. application Ser. No. 09/751,691, now U.S. Pat. No. 6,503,556 filedon Dec. 28, 2000.

Additionally, U.S. application Ser. No. 10/856,984 is also acontinuation-in-part of U.S. application Ser. No. 10/751,043 filed onJan. 2, 2004, which is a continuation of U.S. application Ser. No.09/750,595, now U.S. Pat. No. 6,790,228, which was filed on Dec. 28,2000.

U.S. application Ser. No. 12/766,758 is also a continuation-in-part ofU.S. application Ser. No. 12/363,538, now U.S. Pat. No. 8,007,858, whichwas filed on Jan. 30, 2009, which is a continuation of U.S. applicationSer. No. 10/040,538, now U.S. Pat. No. 7,504,125, which was filed onDec. 28, 2001, which is a continuation-in-part of U.S. application Ser.No. 09/894,293, filed on Jun. 27, 2001, now abandoned, which is acontinuation-in-part of U.S. application Ser. No. 09/844,522, filed onApr. 27, 2001, now U.S. Pat. No. 6,818,247. All of the aforementionedpatent applications and patents are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods for coating stents.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses that areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel. Astent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices that function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of a bodily passage or orifice. In suchtreatments, stents reinforce body vessels and prevent restenosisfollowing angioplasty in the vascular system. “Restenosis” refers to thereoccurrence of stenosis in a blood vessel or heart valve after it hasbeen treated (as by balloon angioplasty, stenting, or valvuloplasty)with apparent acute success.

Stents are typically composed of scaffolding that includes a pattern ornetwork of interconnecting structural elements or struts, formed fromwires, tubes, or sheets of material rolled into a cylindrical shape.This scaffolding gets its name because it physically holds open and, ifdesired, expands the wall of the passageway. Typically, stents arecapable of being compressed or crimped onto a catheter so that they canbe delivered to and deployed at a treatment site. Delivery includespassing the stent through anatomical lumens using a catheter andtransporting it to the treatment site. Deployment includes expanding thestent to a larger diameter once it is at the desired location.Mechanical intervention with stents has reduced the rate of restenosisas compared to balloon angioplasty. Yet, restenosis remains asignificant problem. When restenosis does occur in the stented segment,its treatment can be challenging, as clinical options are more limitedthan for those lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy usesmedicated stents to locally administer a therapeutic substance.Effective concentrations at the treated site require systemic drugadministration that can produce adverse or even toxic side effects.Local delivery is a preferred treatment method because it administerssmaller total medication levels than systemic methods, but concentratesthe drug at a specific site. Local delivery thus produces fewer sideeffects and achieves better results.

A medicated stent may be fabricated by coating the surface of a stentwith an active agent or an active agent and a polymeric carrier. Thoseof ordinary skill in the art fabricate coatings by applying a coatingcomposition that includes a polymer, or a blend of polymers, to thestent using well-known techniques. Such a coating composition mayinclude a polymer solution and an active agent dispersed in thesolution. The composition may be applied to the stent by immersing thestent in the composition or by spraying the composition onto the stent.Removal of all or most of the solvent leaves on the stent surfaces apolymer coating impregnated with the drug or active agent.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include: a method ofcoating a stent, comprising: applying a composition to a stentsubstrate, the composition including a polymer component and a solvent;exposing the polymer component to a temperature equal to or greater thana Tg of the polymer component, wherein the exposing removes solvent fromthe applied composition; and repeating the applying and exposing one ormore times to form a coating, wherein the solvent content of the coatingafter the final exposing step is at a level suitable for a finishedstent.

Further embodiments of the present invention include a method of coatinga stent, comprising: applying a composition to a stent substrate, thecomposition including a polymer component and a solvent; thermallytreating the applied composition, wherein the thermal treatment removessolvent from the applied composition; and repeating the applying andthermal treatment one or more times to form a coating, wherein aduration of each of the thermal treatments is less than 60 seconds (s).

Additional embodiments of the present invention include a method ofmaking a stent, comprising: depositing a composition onto a stentsubstrate, the composition including a polymer component and a solvent;blowing a heated gas onto the deposited composition, wherein the heatedgas removes solvent from the deposited composition; and repeating theapplying and thermal treatment one or more times to form a coating,wherein the coating comprises less than 2 wt % solvent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a three-dimensional view of a cylindrically-shaped stent.

FIG. 2A depicts a cross-section of a stent surface with a drug-polymerlayer.

FIG. 2B depicts a cross-section of a stent surface with a primer layerand a drug-polymer layer.

FIG. 3 depicts an exemplary schematic embodiment of an apparatus forspray coating a stent and in-process drying of the stent.

FIG. 4 depicts the acetone residual level on as coated stent atdifferent interpass drying and control conditions.

FIG. 5 depicts drug release profiles.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention relate to coating implantablemedical devices such as stents. More generally, embodiments of thepresent invention may also be used in coating devices including, but notlimited to, self-expandable stents, balloon-expandable stents,stent-grafts, vascular grafts, drug coated balloons, cerebrospinal fluidshunts, pacemaker leads, closure devices for patent foramen ovale, andsynthetic heart valves. Even more generally, embodiments of the presentinvention may also be used for scaffolding or non-scaffolding purpose inthe area of luminal application, vascular application, and correction,augmentation, fixing, and drug targeting of soft tissue and hard tissue.

In particular, a stent can have virtually any structural pattern that iscompatible with a bodily lumen in which it is implanted. Typically, astent is composed of a pattern or network of circumferential andlongitudinally extending interconnecting structural elements or struts.In general, the struts are arranged in patterns, which are designed tocontact the lumen walls of a vessel and to maintain vascular patency. Amyriad of strut patterns are known in the art for achieving particulardesign goals. A few of the more important design characteristics ofstents are radial or hoop strength, expansion ratio or coverage area,and longitudinal flexibility. Embodiments of the present invention areapplicable to virtually any stent design and are, therefore, not limitedto any particular stent design or pattern. One embodiment of a stentpattern may include cylindrical rings composed of struts. Thecylindrical rings may be connected by connecting struts.

In some embodiments, a stent may be formed from a tube by laser cuttingthe pattern of struts in the tube. The stent may also be formed by lasercutting a metallic or polymeric sheet, rolling the pattern into theshape of the cylindrical stent, and providing a longitudinal weld toform the stent. Other methods of forming stents are well known andinclude chemically etching a metallic or polymeric sheet and rolling andthen welding it to form the stent.

In other embodiments, a metallic or polymeric filament or wire may alsobe coiled to form the stent. Filaments of polymer may be extruded ormelt spun. These filaments can then be cut, formed into ring elements,welded closed, corrugated to form crowns, and then the crowns weldedtogether by heat or solvent to form the stent.

FIG. 1 illustrates a conventional stent 10 formed from a plurality ofstruts 12. The plurality of struts 12 are radially expandable andinterconnected by connecting elements 14 that are disposed betweenadjacent struts 12, leaving lateral openings or gaps 16 between adjacentstruts 12. Struts 12 and connecting elements 14 define a tubular stentbody having an outer, tissue-contacting surface and an inner surface.

The cross-section of the struts in stent 10 may be rectangular- orcircular-shaped. The cross-section of struts is not limited to these,and therefore, other cross-sectional shapes are applicable withembodiments of the present invention. Furthermore, the pattern shouldnot be limited to what has been illustrated as other stent patterns areeasily applicable with embodiments of the present invention.

A medicated stent may be fabricated by coating the surface of a stentwith a drug. For example, a stent can have a coating including a drugdispersed in a polymeric carrier disposed over a substrate. FIG. 2Adepicts a cross-section of a stent surface with a drug-polymer coatinglayer 210 over a substrate 200. In other embodiments, drug-polymer layer210 can be disposed over a polymeric coating layer. In some embodiments,coating layer 210 can also be pure drug. Coating layer 210 includes adrug 220 dispersed in a coating polymer 230. As indicated above, asubstrate or scaffolding can be metallic, polymeric, ceramic, or othersuitable material.

FIG. 2B depicts a cross-section of a substrate 240 of a stent with apolymeric layer 250 disposed over substrate 240. A drug-polymer coatinglayer 260 is disposed over polymeric layer 250. Coating layer 260includes a drug 270 dispersed within a polymer 280. Polymeric layer 250can be a primer layer for improving the adhesion of drug-polymer layer260 to substrate 240.

As indicated above, a coating on a stent may be formed by applying ordepositing a coating composition including polymer dissolved in asolvent on the stent substrate, body, or scaffolding. The coatingcomposition can optionally also include a therapeutic agent or drug orother substance, for example, a radiopaque agent.

The coating composition can be applied to a substrate by variousmethods, such as, dip coating, brushing, or spraying. The embodiments ofthe present invention are not limited to any particular application ordeposition technique. In particular, spray coating a stent typicallyinvolves mounting or disposing a stent on a support, followed byspraying a coating composition from a nozzle onto the mounted stent.Solvent is removed from the deposited coating composition to form thecoating. There typically is some residual solvent remaining in thecoating after the solvent removal or solvent removal steps. As discussedin more detail below, solvent removal can be performed throughevaporation at room or ambient temperature or with a thermal treatmentthat includes heating or exposing a coated stent to a temperature aboveroom temperature. Room or ambient temperature may be between 20 and 30°C. and any temperature in between.

If a coating layer of a target thickness (or mass) is formed with asingle application step and then followed by solvent removal, thecoating layer that results can be nonuniform, include coating defects,or both. Stents, particularly those for coronary use, comprise anintricate stent pattern with small dimensions. If sufficient coating isapplied all at once to load the desired amount of drug, the appliedsolution will form webs, pools, or strands in the stent pattern. Insteadof the desired conformal coating, a highly non-uniform coating results.Therefore, a coating of a target thickness (or mass) is preferablyformed with two or more cycles or passes of a coating compositionapplication, such as spraying. After each cycle or pass, a solventremoval or drying step is performed. The solvent removal step after eachpass is referred to as interpass drying. A cycle or pass refers to theapplication of a coating composition without an intervening solventremoval step, such as blowing warm air on the stent. In spraying, acycle or pass can include directing the spray plume over the length of astent one or more times. After each coating composition applicationpass, the application of coating composition on the substrate isstopped, which is followed by interpass solvent removal.

FIG. 3 depicts an exemplary schematic embodiment of an apparatus forspray coating a stent and in-process drying of the stent. During thecoating process, a stent 305 is shifted back and forth between spraycoating apparatus 300 and drying station 400. In spray coating apparatus300, a syringe pump 310 pumps coating material from a reservoir 315 thatis in fluid communication with a spray nozzle 320. Nozzle 320 can be influid communication with pump 310 through a tubing 325. Nozzle 320provides a plume 330 of fine droplets of coating material for depositingon stent 305. Nozzle 320 is positioned a distance (Dn) from the surfaceof stent 305. A flow rate of coating material provided by pump 310 canbe varied by changing the pump rate of pump 310.

Stent 305 is supported by a stent support 335, such as a mandrel.Support 335 can be configured to rotate stent 305 about its cylindricalaxis, as shown by an arrow 340. Support 335 can also be configured toaxially or linearly translate stent 305 with respect to plume 330, asshown by an arrow 345. As an alternative, nozzle 320 can be linearlytranslated with respect to stent 305. Further, both nozzle 320 and stent305 can be simultaneously or independently linearly translated withrespect to each other.

Stent 305 may pass nozzle/plume 320, 330 completely in one lineardirection 345 to receive coating material, and then be directed in thereverse linear direction 345 past nozzle/plume 320, 330 to receiveadditional coating material.

As shown by arrow 360, stent 305 and support 335 are shifted to aposition 490 to drying station 400. Drying station 400 includes a gassource 410, a flow controller 420 (e.g., a flow controller availablefrom MKS Instruments, Wilmington, Mass.), an in-line heater 440 (e.g.,an in-line heater available from Sylvania, Danvers, Mass.), a computercontroller 460, and a nozzle 450. Computer controller 460 can be incommunication with flow controller 420 and in-line heater 440 to controlthe amount of air and temperature, respectively, which is delivered tonozzle 450. In-line heater 440 can be used to precisely and graduallyincrease the temperature of the gas delivered by gas source 400 to thetemperature used to conduct the drying. Nozzle 450 directs a heated gasstream 480 at stent 305 with applied coating material that is inposition 490. Stent 305 and support 335 are shifted back to spraycoating apparatus 300 for further coating application when the interpassdrying step is completed.

The residual solvent content in the coating after interpass dryingdepends on factors such the coating formulation and the boiling point ofthe solvent. For a PDLLA-acetone formulation, the residual solventcontent may be 4-7 wt % with no drying. For other formulations thatinclude low volatility solvents, the solvent content could be as high as10 wt %.

Each pass results in the formation of a coating layer of a giventhickness that contains a residual amount of solvent. The multiplepasses result in the formation of a coating composed of multiple layers,the combined thickness of the multiple layers being the target thicknessof the coating. Any suitable number of repetitions of applying thecomposition followed by removing the solvent(s) can be performed to forma coating of a desired thickness or mass. Excessive application of thepolymer can, however, cause coating defects.

As indicated above, interpass solvent removal, as used herein, alsoincludes the solvent removal after the last coating compositionapplication or last pass. Interpass solvent removal can be characterizedas removal of solvent from a “wet” coating, wherein a wet coating refersto a deposited coating composition. After interpass solvent removal ordrying of a wet coating layer, the coating may be characterized as a“dry” coating layer, although it contains residual solvent not removedby interpass drying.

After the final interpass coating composition application and interpasssolvent removal, the dry coating may is typically subjected to aterminal solvent removal step to remove a significant portion ofresidual solvent. This terminal solvent removal step can becharacterized as solvent removal from a dry coating. The terminalsolvent removal treatment from the dry coating is typicallysignificantly longer than the interpass solvent removal from the wetcoating. Conventionally, the solvent removal from a dry coating isperformed by baking the coated stent.

When spraying is used for application of coating composition, each passor repetition can be, for example, about 0.5 second to about 20 secondsin duration. The amount of coating solids applied by each repetition canbe about 1 microgram/cm² (of stent surface area) to about 100micrograms/cm².

Interpass solvent removal results in a significant amount of thesolvent(s) removed. For example, interpass solvent removal results acoating layer containing less than 5 wt %, 3 wt %, or more narrowly,less than 1 wt % of solvent remaining in the layer. The solvent contentafter terminal solvent removal depends on factors such the coatingformulation and the boiling point of the solvent. For a PDLLA-acetoneformulation, the residual solvent content may be less than 2 wt %. Forother formulations that include low volatility solvents, the solventcontent could be as high as 5 wt %.

Conventionally, the interpass solvent removal is not sufficient toreduce the residual solvent content of the coating to that of a finishedcoating. The shorter interpass solvent removal reduces process time,increasing manufacturing throughput, while allowing formation of auniform multilayer coating. The duration of the terminal solvent removalprocess is significantly longer than the interpass drying in order toreduce the solvent content to the target solvent content.

Interpass solvent removal may be achieved by allowing the solvent toevaporate at room or ambient temperature. The time to remove solvent toa target solvent content depends in part on the volatility of thesolvent. The solvent removal time for the interpass solvent removal canbe decreased by subjecting the stent substrate with the applied coatingcomposition to a thermal treatment process. Additionally, the terminalsolvent removal can be achieved using a thermal treatment process.

A thermal treatment process includes exposing the stent substrate withapplied coating composition, in the case of interpass drying, or thestent substrate with a coating having residual solvent, to a temperaturegreater than room or ambient temperature. A thermal treatment processcan include blowing a heated gas on the stent substrate with the coatingcomposition or coating. The thermal treatment process can also includebaking the stent substrate with the applied coating composition orcoating with residual solvent in an oven. A typical process includesused the heated gas for interpass solvent removal and baking for theterminal solvent removal.

In the heated gas interpass solvent removal, the stent may be positionedbelow a nozzle blowing the heated or warm gas. By way of example, warmgas applications can be performed at a flow speed of less than about5,000 feet/minute, and for about 10 seconds. The gas can be directedonto the stent following a waiting period of about 0.1 second to about 5seconds after the application of the coating composition so as to allowthe liquid sufficient time to flow and spread over the stent surfacebefore the solvent(s) is removed to form a coating. The waiting periodis particularly suitable if the coating composition contains a volatilesolvent since such solvents are typically removed quickly. As usedherein “volatile solvent” means a solvent that has a vapor pressuregreater than 17.54 Torr at ambient temperature, and “non-volatilesolvent” means a solvent that has a vapor pressure less than or equal to17.54 Torr at ambient temperature. In terminal solvent removal, a stentis typically dried in an oven as the final drying step when thedeposition stages are completed. The time for solvent removal istypically much longer than interpass solvent removal. For example, astent can be baked in an oven at a mild temperature (e.g., 40-50° C.)for a suitable duration of time (e.g., 30 min-4 hours) or by theapplication of warm air.

Various embodiments of the present invention include performing theinterpass drying in a manner that provides a target solvent content inthe coating with reduced terminal solvent removal time or no terminalsolvent removal, for example, no baking step. There are significantadvantages to reducing the time of or eliminating the terminal solventremoval step. First, such embodiments will improve the productionthroughput and reduce the equipment and labor costs due to the removalof the baking step. Second, the risk of adverse effects on the surfaceand bulk properties on the polymer of the coating and polymer substratefrom prolonged baking will be reduced or eliminated. Third, there is abenefit in knowing the final “dry” stent weight immediately followingthe spray/dry process. Spray process corrections can happen more quicklyand with improved accuracy by having the dry stent weight immediatelyrather than having the weight 30-60 min after the coating, a typicaltime for terminal drying in an oven.

The second advantage is particularly important for stents havingbioabsorbable polymer substrates over which coatings are formed and alsofor bioabsorbable polymer coatings over both polymer and metallicsubstrates. Bioabsorbable polymer substrates are designed to providemechanical support to lumen walls for a period of time and then degradeand dissolve away from the implant site. The mechanical and degradationproperties can be sensitive to exposure to elevated temperatures forprolonged periods. Additionally, the surface and degradation propertiesof bioabsorbable polymeric coatings can also be sensitive to theprolonged exposure to elevated temperatures of a terminal solventremoval step, such as baking Preserving the surface and bulk propertiesof the bioabsorbable coating and stent materials are critical to theoverall performance of the stent. Exemplary polymers that can be used asa bioabsorbable substrate or in a coating include, but are not limitedto, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLA), and polyglycolide(PGA). Random or alternating copolymers or block copolymers of the abovepolymers with each other or other polymers may also be used, forexample, poly(D,L-lactide-co-glycolide), andpoly(L-lactide-co-glycolide) (PLGA). For PLGA, any molar proportion ofL-lactide to glycolide is included, such as, 90:10, 75:25, 50:50, 25:75,and 10:90.

As shown in Table 1 below, the above polymers have glass transitiontemperatures (Tg) above room or ambient temperature. PLLA, PDLA, and awide range of PLGA compositions have a Tg above human body temperature.Human body temperature is approximately 37° C. These Tgs are for thepolymers with minimal solvent content (<1% w/w) and a moisture contentin equilibrium with typical ambient conditions. The Tg range for PGA isabove and below human body temperature.

TABLE 1 Glass transition temperatures and melting points of polymers.Polymer Melting Point (° C.)¹ Glass-Transition Temp (° C.)¹ PGA 225-23035-40 PLLA 173-178 60-65 PDLA Amorphous 55-60 85/15 PLGA Amorphous 50-5575/25 PLGA Amorphous 50-55 65/35 PLGA Amorphous 45-50 50/50 PLGAAmorphous 45-50 ¹Medical Plastics and Biomaterials Magazine, March 1998.

The substrate and coatings can also be made from random or alternatingor block copolymers of the above polymers with polymers having Tg'sbelow room or body temperature including, but not limited to,polycaprolactone (PCL), poly(trimethylene carbonate) (PTMC),polydioxanone (PDO), poly(4-hydroxy butyrate) (4-PHB),poly(3-hydroxybutyrate) (3-PHB), and poly(butylene succinate) (PBS).

An exemplary stent includes a stent substrate or backbone made of PLLAand a coating that includes Everolimus drug and PDLA polymer, forexample, with a 1:1 weight ratio. The coating for this stent can beformed by methods of the present invention. The coating composition (4wt % drug and polymer in acetone, drug to polymer ratio of 1:1) issprayed over the stent.

A coating process includes an interpass or inprocess dry station. Aconventional coating process includes an interpass drying and a finaloven bake. The interpass drying is 15 seconds per dry cycle at 40° C. toremove most of the solvent from the coating and a final oven bake at 50°C. with the oven time at 30 to 60 minutes.

In this conventional process, a two-stage weight loss profile of theresidual solvent from the coating has been observed when a coated stentis baked in an oven. In the first stage, the weight vs. time decreasessteeply, corresponding to a rapid loss of residual solvent. The weightvs. time then levels off gradually after a few minutes and in a secondstage, the weight decreases gradually during the remainder of the ovenbake. The evaporation rate of the solvent in the first stage is believedto be governed by several variables including surface to volume ratio,vapor pressure, surface temperature, and air flow over the surface.

During the second stage, it is believed that the solvent loss isdependent primarily on the rate of diffusion of the solvent moleculesthrough the coating. The diffusion rate is primarily controlled by thefree volume availability of the polymer. The diffusion mechanism isbelieved to be the solvent molecules jumping from one free volume holeto another. In such a mechanism, it is believed that the most importantfactor in affecting the free volume is the temperature differencebetween the processing temperature of the thermal treatment (e.g.,baking temperature) (Tp) and the Tg of the polymer of the coatingmaterial (Tp−Tg).

As indicated above, embodiments of the present invention includeperforming the interpass drying in a manner that provides a targetsolvent content in the coating with reduced terminal solvent removaltime or no terminal solvent removal, for example, no baking step. Insome embodiments, the target solvent content in the coating after thefinal interpass drying step is at a level suitable for a finished stent.In other embodiments, the target solvent content in the coating after areduced terminal solvent removal time (e.g., baking time) is at a levelsuitable for a finished stent.

In embodiments of the invention, a coating composition is applied to astent substrate that includes a polymer in a solvent. Certainembodiments of the present invention include performing at least oneinterpass solvent removal step with a thermal treatment in which atarget temperature is greater than or equal to the Tg of the polymer ofthe coating. An interpass thermal treatment includes heating or exposinga polymer of the applied composition to a target or process temperature.In some embodiments, the process temperature for all or each of theinterprocess solvent removal steps is greater than or equal to the Tg ofthe polymer of the coating composition.

In certain embodiments, the interpass thermal treatment includes heatingto or exposure of the coating to the target or process temperature for aprocess time between 0-5 s, 0-10 s, 0-30 s, 0-60 s, 0-2 min, or lessthan 5 min. In other embodiments, the process time is between 0-5 s,5-10 s, 10-15 s, 15-30 s, 30-60 s, 60 s-2 min, or 2-5 min. In additionalembodiments, the process time is less than 5 s, 10 s, 15 s, 30 s, 60 s,2 min, or 5 min. The thermal treatment in a preferred embodiment isblowing a warm gas on the stent. In this preferred embodiment, theblowing of the warm gas on the stent is performed for one of the abovetime periods.

In some embodiments, the polymer has a Tg greater than room temperature.In other embodiments, the polymer also has a Tg greater than human bodytemperature. In additional embodiments, the polymer is a block copolymerhaving at least one block with a Tg greater than room temperature oradditionally greater than human body temperature. In this case, thethermal treatment temperature of the interpass solvent removal isgreater than the Tg of the block or all blocks having a Tg greater thanroom or also human body temperature.

In further embodiments, a stent fabrication process including two ormore coating composition application steps and a corresponding interpasssolvent removal thermal treatment includes a terminal solvent removalstep, such as baking, for less than 30 min, less than 20 min, less than10 min, less than 5 min, or less than 2 min. The terminal solventremoval step may be 20-30 min, 10-20 min, 5-10 min, or 2-5 min. In suchembodiments, no additional solvent removal step is performed after theterminal solvent removal step. Alternatively, no additional thermaltreatment involving exposure of the stent to temperature greater than40° C. is performed. Alternatively or additionally, no additionalthermal treatment involving exposure for greater than 30 s, 60 s, 2 min,or greater than 5 min is performed on the stent.

In other embodiments, no terminal solvent removal step, such as baking,is performed after the last interpass solvent removal step in a stentfabrication process including two or more coating compositionapplication steps and a corresponding interpass solvent removal thermaltreatment. In such embodiments, no additional solvent removal step maybe performed after the final interpass solvent removal step.Alternatively, no additional thermal treatment involving exposure of thestent to a temperature greater than 40° C. is performed. Alternativelyor additionally, no additional thermal treatment involving exposure forgreater than 30 s, 60 s, 2 min, or greater than 5 min is performed onthe stent.

The target solvent content of the coating after the last interpasssolvent removal step or after the reduced duration terminal solventremoval step may be less than 5 wt %, 4 wt %, 3, wt %, 2 wt %, 1 wt %,or less than 0.05 wt % of the coating. Additionally, the target solventcontent of the coating after the last interpass solvent removal step maybe 0.05-1 wt %, 1-2 wt %, 2-3 wt %, 3-4 wt %, and 4-5 wt % of thecoating.

The process temperature for interpass drying may be Tg or slightly aboveTg or more. For example, Tp−Tg may be less than 1° C., 3° C., 5° C., 7°C., 10° C., 12° C., 15° C., or less than 20° C. Additionally, the Tp−Tgmay be 1-3° C., 3-5° C., 5-7° C., 7-10° C., 10-12° C., 12-15° C., or15-20° C. In addition, the process temperature can be any temperature orrange that is above Tg and also between room temperature and 90° C. Theupper limit of the process temperature may be limited by considerationssuch as degradation of a drug in the coating, degradation of the coatingpolymer, or degradation of properties of the substrate polymer. Drugswith a propensity to oxidation typically start to degrade between80-100° C., so the process temperature should less than this range.However, there may be drugs which start to degrade at temperatureshigher than this range, thus a higher process temperature may be used.

The amount of solvent removal, and thus, the solvent content of thecoating after interpass drying depends on both the process time andtemperature. In general, the longer the process time, the higher theprocess temperature, or both, the greater the solvent removal and lowerthe solvent content of the coating. Embodiments of the inventioninclude, a process time and temperature combination and selectionthereof that provides a target solvent content of the coating, such asthe values and ranges of target solvent content disclosed herein. Anycombination of the process time and temperature values or ranges areembodiments of the invention. It is neither known or predictable thatthere exist combinations of process time and temperature that canprovided particular desired target solvent content of a coating with areduced terminal thermal treatment (e.g., reduced baking time) or noterminal thermal treatment (e.g., no baking).

In the interpass drying, the stent may be positioned below a nozzleblowing the warm gas. A warm gas may be particularly suitable forembodiments in which the solvent employed in the coating composition isa non-volatile solvent (e.g., dimethylsulfoxide (DMSO),dimethylformamide (DMF), and dimethylacetamide (DMAC)).

Any suitable gas can be employed, examples of which include air, argon,or nitrogen. The flow rate of the warm gas can be from about 20 cubicfeet/minute (CFM) (0.57 cubic meters/minute (CMM)) to about 80 CFM (2.27CMM), more narrowly about 30 CFM (0.85 CMM) to about 40 CFM (1.13 CMM).The warm gas can be applied for about 3 seconds to about 60 seconds,more narrowly for about 10 seconds to about 20 seconds. By way ofexample, warm air applications can be performed at a temperature ofabout 50° C., at a flow rate of about 40 CFM, and for about 10 seconds.

A spray apparatus, such as EFD 780S spray device with VALVEMATE 7040control system (manufactured by EFD Inc., East Providence, R.I., can beused to apply a composition to a stent. A EFD 780S spray device is anair-assisted external mixing atomizer. The composition is atomized intosmall droplets by air and uniformly applied to the stent surfaces. Othertypes of spray applicators, including air-assisted internal mixingatomizers and ultrasonic applicators, can also be used for theapplication of the composition.

To facilitate uniform and complete coverage of the stent during theapplication of the composition, the stent can be rotated about thestent's central longitudinal axis. Rotation of the stent can be fromabout 0.1 rpm to about 300 rpm, more narrowly from about 30 rpm to about200 rpm. By way of example, the stent can rotate at about 150 rpm. Thestent can also be moved in a linear direction along the same axis. Thestent can be moved at about 1 mm/second to about 12 mm/second, forexample about 6 mm/second, or for a minimum of at least two passes(i.e., back and forth past the spray nozzle).

A nozzle can deposit coating material onto a stent in the form of finedroplets. An atomization pressure of a sprayer can be maintained at arange of about 5 psi to about 30 psi. The droplet size depends onfactors such as viscosity of the solution, surface tension of thesolvent, atomization pressure, and flow rate. The flow rate of thecomposition from the spray nozzle can be from about 0.01 mg/second toabout 1.0 mg/second, for example about 0.1 mg/second. Only a smallpercentage of the composition that is delivered from the spray nozzle isultimately deposited on the stent. By way of example, when a compositionis sprayed to deliver about 1 mg of solids, only about 100 micrograms orabout 10% of the solids sprayed will likely be deposited on the stent.

A non-polymer substrate for an implantable medical device may be made ofa metallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum.

In accordance with one embodiment, the coating material can include asolvent and a polymer dissolved in the solvent and optionally a wettingfluid. The coating material can also include active agents, radiopaqueelements, or radioactive isotopes. Representative examples of polymersthat may be used as a substrate of a stent or coating for a stent, ormore generally, implantable medical devices include, but are not limitedto, poly(N-acetylglucosamine) (Chitin), Chitosan,poly(3-hydroxyvalerate), poly(L-lactide-co-glycolide),poly(3-hydroxybutyrate), poly(4-hydroxybutyrate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lacticacid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),poly(L-lactide-co-D,L-lactide), poly(caprolactone),poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(trimethylene carbonate), polyesteramide, poly(glycolic acid-co-trimethylene carbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, biomolecules(such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid), polyurethanes, silicones, polyesters, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymersand copolymers, vinyl halide polymers and copolymers (such as polyvinylchloride), polyvinyl ethers (such as polyvinyl methyl ether),polyvinylidene halides (such as polyvinylidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such aspolystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose. Additional representative examples of polymers that may beespecially well suited for use in fabricating embodiments of implantablemedical devices disclosed herein include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluoropropene) (e.g., SOLEF 21508, available from SolvaySolexis PVDF, Thorofare, N.J.), polyvinylidene fluoride (otherwise knownas KYNAR, available from ATOFINA Chemicals, Philadelphia, Pa.),ethylene-vinyl acetate copolymers, poly(vinyl acetate),styrene-isobutylene-styrene triblock copolymers, and polyethyleneglycol.

Examples of solvents include, but are not limited to, dimethylsulfoxide(DMSO), chloroform, acetone, water (buffered saline), xylene, methanol,ethanol, 1-propanol, tetrahydrofuran, 1-butanone, dimethylformamide,dimethylacetamide, cyclohexanone, ethyl acetate, methylethylketone,propylene glycol monomethylether, isopropanol, isopropanol admixed withwater, N-methyl pyrrolidinone, toluene, and combinations thereof.

A “wetting” of a fluid is measured by the fluid's capillary permeation.Capillary permeation is the movement of a fluid on a solid substratedriven by interfacial energetics. Capillary permeation is quantified bya contact angle, defined as an angle at the tangent of a droplet in afluid phase that has taken an equilibrium shape on a solid surface. Alow contact angle means a higher wetting liquid. A suitably highcapillary permeation corresponds to a contact angle less than about 90°.Representative examples of the wetting fluid include, but are notlimited to, tetrahydrofuran (THF), methanol, dimethylformamide (DMF),1-butanol, n-butyl acetate, dimethylacetamide (DMAC), and mixtures andcombinations thereof.

Examples of radiopaque elements include, but are not limited to, gold,tantalum, and platinum. An example of a radioactive isotope is P³².Sufficient amounts of such substances may be dispersed in thecomposition such that the substances are not present in the compositionas agglomerates or flocs.

Examples of active agents include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; orCOSMEGEN available from Merck). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. The bioactive agent can also fall under the genus ofantineoplastic, anti-inflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel, (e.g., TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g., Taxotere®, from Aventis S.A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includeaspirin, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax a (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.,Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g., Prinivil® and Prinzide® from Merck &Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, proteins, peptides, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate agents include cisplatin,insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin,alpha-interferon, genetically engineered epithelial cells, steroidalanti-inflammatory agents, non-steroidal anti-inflammatory agents,antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, estradiol, antibiotics, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, ABT-578, clobetasol, cytostatic agents,prodrugs thereof, co-drugs thereof, and a combination thereof. Othertherapeutic substances or agents may include rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, methyl rapamycin,40-O-tetrazole-rapamycin ABT-578, biolimus, deforolimus, temsirolimus,myolimus, and novolimus.

The “glass transition temperature,” Tg, is the temperature at which theamorphous domains of a polymer change from a brittle vitreous state to asolid deformable or ductile state at atmospheric pressure. In otherwords, the Tg corresponds to the temperature where the onset ofsegmental motion in the chains of the polymer occurs. When an amorphousor semicrystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is raised the actual molecular volume in thesample remains constant, and so a higher coefficient of expansion pointsto an increase in free volume associated with the system and thereforeincreased freedom for the molecules to move. The increasing heatcapacity corresponds to an increase in heat dissipation throughmovement. Tg of a given polymer can be dependent on the heating rate andcan be influenced by the thermal history of the polymer. Furthermore,the chemical structure of the polymer heavily influences the glasstransition by affecting mobility.

EXAMPLE

The following example illustrates interpass drying with no baking stepand the influence of thermal treatment temperature and treatmentduration on solvent removal from a bioabsorbable coating over abioabsorbable stent substrate. The stent substrate was PLLA and thecoating is a 1:1 ratio by weight of Everolimus drug and PDLA polymer (Tgis about 55 to about 60° C.). The coating composition was 4 wt % drugand polymer in acetone, 1/1 drug to polymer, which was sprayed over thestent substrate. In between coating composition applications, theapplied composition is heated in an in-process dry station to removesolvent from the applied coating composition. A heated gas is blown ontothe stent at the interpass dry station.

Table 2 lists the residual acetone level of the coated stent at variousinterpass dry temperatures and interpass dry times. The first two rows,Group 7, is the Control which represents results of the solvent removalthat includes both interpass drying and baking. The first row representssolvent removal at the interpass dry station with a temperature of 40°C., below the Tg of the coating polymer. At the end of the coatingapplication passes, the stent is baked at 50° C. for 30 minutes. Groups1 to 6 are the results for interpass drying without any oven bake atthree different temperatures and two treatment durations pertemperature.

FIG. 4 and Table 2 show the acetone residual level on as coated stentsat different interpass drying and control conditions. As shown in FIG. 4and Table 2, the interpass dry temperature at 70° C. and interpass drytime 10 seconds (Group 6) achieves the same acetone residual level (SeeFIG. 4) as the Control. Thus, interpass drying above Tg of the coatingpolymer can replace the Control process that uses a combination ofinterpass drying and an oven bake step, both below Tg of the coatingpolymer. The final acetone level of the Group 6 finished product is wellwithin the target specification. No additional drug (Everolimus)degradation was detected from this study using the elevated interpassdry temperatures between 50 and 70° C.

TABLE 2 Results for solvent removal at various temperatures and times.Average residual Average residual Study Group (n = 3) acetone, μg/stentacetone, % Group 7-Control 8.8 ± 1.8 2.5 (as coated, 40° C. 15 s) Group7-Control 3.0 ± 0.1 0.9 (with 50° C. oven/ 30 min) Group 1 7.8 ± 0.5 2.2(50° C./15 seconds) Group 2 7.3 ± 0.2 2.2 (50° C./25 seconds) Group 36.0 ± 0.6 1.8 (60° C./15 seconds) Group 4  6.3 ± 0.21 1.9 (60° C./25seconds) Group 5 3.2 ± 0.2 1.0 (70° C./15 seconds) Group 6 3.6 ± 0.7 1.0(70° C./I0 seconds)

FIG. 5 depicts drug release profiles for Groups in Table 2. The drugrelease profiles and rates were very similar among the groups.

Thus, by drying the coating at a temperature slightly above the Tg ofthe material, the drying rate can be improved significantly since thelengthy oven bake step is eliminated. Elimination of baking stepdecreases process time and reduces manufacturing cost.

Other potential benefits of removing the oven bake step include reducingthe heat exposure time of the substrate material which may allow it tobetter retain its properties, decrease equipment cost (e.g. eliminateoven and pre-bake balances), decrease direct labor, decrease yield lossincurred in oven-bake step, and decrease batch loss due to power outage.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1-9. (canceled)
 10. A method of fabricating a stent, comprising:thermally treating a stent having a stent body including a compositionapplied to a surface of the stent body, the composition comprising asolvent and a first bioabsorbable polymer, wherein the stent bodycomprises a second bioabsorbable polymer, wherein a glass transitiontemperature (Tg) of the first bioabsorbable polymer is greater thanhuman body temperature, wherein a process temperature of the thermaltreatment is 1 to 20 deg C above the Tg of the first bioabsorbablepolymer, wherein a duration of the thermal treatment is 5 to 30 min; andcrimping the thermally treated stent onto a catheter so that it can bedelivered to and deployed at a treatment site in a blood vessel.
 11. Themethod of claim 10, wherein the second bioabsorbable polymer of thestent body comprises poly(L-lactide-co-caprolactone).
 12. The method ofclaim 10, wherein the second bioabsorbable polymer of the stent bodycomprises poly(L-lactide).
 13. The method of claim 10, wherein the firstbioabsorbable polymer comprises poly(DL-lactide) (PDLA).
 14. The methodof claim 10, wherein the thermal treatment comprises blowing a heatedgas on the stent.
 15. The method of claim 10, wherein the stent is notbaked after the thermal treatment.
 16. The method of claim 10, whereinno additional thermal treatment of the stent is performed after thethermal treatment.
 17. The method of claim 10, wherein the duration ofthe thermal treatment is 5 to 10 min.
 18. The method of claim 10,wherein the duration of the thermal treatment is 10 to 20 min.
 19. Themethod of claim 10, wherein the duration of the thermal treatment is 20to 30 min.
 20. The method of claim 10, wherein the process temperatureof the thermal treatment is 5 to 15 deg C above the Tg of the firstbioabsorbable polymer.
 21. The method of claim 10, wherein the processtemperature of the thermal treatment is 15 to 20 deg C above the Tg ofthe first bioabsorbable polymer.